POS0404 IFNα-MEDIATED METABOLIC REPROGRAMMING IN HUMAN SLE MONOCYTES INVOLVES PERTURBATIONS IN GLYCOLYTIC AND LIPID METABOLISM TO REGULATE PROINFLAMMATORY MARKERS AND CYTOKINES
Authors: C. Stathopoulou, D. Konstantopoulos, S. Papanikolaou, G. Vatsellas, G. Panagopoulos, P. Sidiropoulos, G. Bertsias
Journal: Annals of the Rheumatic Diseases (2022)

Background Systemic Lupus Erythematosus (SLE) is a prototype interferonopathy characterized by multiple organ damage 1 . Metabolomic analyses of patient-derived sera indicate distinct metabolic pertubations in oxidative and lipid metabolism 2,3 . Among innate effectors, monocytes (Mo) are implicated in SLE pathogenesis and also display a perturbed metabolic phenotype 4 . Objectives Based on previous data indicating a prominent IFNα-gene signature in SLE monocytes even during disease remission 5 , we herein sought to delineate the metabolic repercussion of IFNα signaling contributing to SLE autoimmunity. Methods Using transcriptomic data, we compared the enriched metabolic categories of IFNα(+) and IFNα(-) SLE-Mo 6 . In order to compare metabolic perturbations pertaining to SLE, we performed transcriptomic Gene Set Enrichment Analysis (GSEA) 7 from in vitro cultured IFNα-activated Mo. We supplemented the analysis with selective ex vivo biochemical inhibition of the metabolic pathways arising from the GSEA and evaluated the effect on inflammatory markers of healthy IFNα-Mo. Results We found a statistically significant enrichment of transcripts associated with glycolytic metabolism and lipid biosynthetic and catabolic processes in both IFNα(+)-SLE Mo and healthy IFNα-Mo, but not in IFNα(-)-SLE Mo, which in turn resembled healthy-Mo. Additionally, transcripts associated with cholesterol biosynthetic processes such PMVK , SQLE , LSS , DHCR7 , and LDLR , MVK , FFT1 were significantly upregulated in IFNα(+)-SLE Mo and healthy IFNα-Mo respectively. In accordance, blockade of either glycolysis with the use of 2-DG hexokinase inhibitor, or mevalonic acid synthesis with the use of fluvastatin, attenuated proinflammatory cytokine secretion (IL6, CXCL10) associated with IFN-response in both IFNα(+)-SLE Mo and healthy IFNα-Mo. Conclusion Our results link IFNα mediated metabolic shifts in Mo with corresponding metabolic perturbations found in SLE patient-Mo. Pending further confirmation with targeted metabolomics, these data further rationalize the use of IFN blockade and also suggest the potential use of specific metabolites as novel therapeutic targets in SLE. References [1]Crampton, S. P., Morawski, P. A. &amp; Bolland, S. Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus. Dis. Model. Mech. 9, 1033–1046 (2014). [2]Yan, B. et al. Serum metabolomic profiling in patients with systemic lupus erythematosus by GC/MS. Mod. Rheumatol. 26, 914–922 (2016). [3]Gkirtzimanaki, K. et al. IFNα impairs autophagic degradation of mtDNA promoting autoreactivity of SLE monocytes in a STING-dependent fashion. Cell Rep. 25, 921-933.e5 (2018). [4]Huang, N. &amp; Perl, A. Metabolism as a target for modulation in autoimmune diseases. Trends Immunol. 39, 562–576 (2018). [5]Panousis, N. I. et al. Combined genetic and transcriptome analysis of patients with SLE : distinct, targetable signatures for susceptibility and severity. Ann. Rheum. Dis. 78, 1079–1089 (2019). [6]El-Sherbiny, Y. M. et al. A novel two-score system for interferon status segregates autoimmune diseases and correlates with clinical features. Sci. Rep. 8, 5793 (2018). [7]Subramanian, A. et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. 102, 15545–15550 (2005). Disclosure of Interests None declared.